Increased risk of death associated with the use of proton-pump inhibitors in patients with dementia and controls - a pharmacoepidemiological claims data analysis.

BACKGROUND AND PURPOSE: The use of proton-pump inhibitors (PPIs) was reported to be associated with increased mortality risk and has been proposed as a potential risk factor for neurodegenerative diseases. We aimed to assess the impact of PPI use on survival in patients with dementia as compared with controls. METHODS: This register-based control-matched cohort study included 28 428 patients with dementia ascertained by the prescription of antidementia drugs and two control individuals matched by sex, age and area of residence for each patient with dementia during the study period from 1 January 2005 to 30 June 2016. Cumulative defined daily doses (DDDs) of PPIs were extracted from the health insurance prescription registries. A multivariate Cox regression model for non-proportional hazards was used to analyse mortality risk in dependence of PPI exposure, which was limited to 1 year preceding the date of cohort entry (index date) in order to avoid immortal time bias. RESULTS: The PPI exposure of 100 DDDs in the year before the index date was associated with an increased mortality risk in patients with dementia (adjusted hazard ratio, 1.07; 95% confidence intervals, 1.03-1.12), but also in controls (adjusted hazard ratio, 1.47; 95% confidence intervals, 1.31-1.64). The mortality risk in relation to PPI use was significantly lower in patients with dementia as compared with controls (P < 0.0001) and highest in the first 2 years after the index date in both cohorts. CONCLUSIONS: Our findings promote more stringent pharmacovigilance strategies to avoid PPI use in cases lacking a clear indication for therapy or where potential risks outweigh the benefits.

Argyrophilic grain disease in individuals younger than 75 years: clinical variability in an under-recognized limbic tauopathy.

BACKGROUND AND PURPOSE: Argyrophilic grain disease (AGD) is a limbic-predominant 4R-tauopathy. AGD is thought to be an age-related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75. METHODS: Patients were identified retrospectively based on neuropathological examinations during 2006-2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records. RESULTS: In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51-74) and the median duration of disease was 3 months (range 0.5-36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy. CONCLUSIONS: Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau-based therapeutic strategies.

Genotype-guided diagnostic reassessment after exome sequencing in neuromuscular disorders: experiences with a two-step approach.

BACKGROUND AND PURPOSE: Next-generation sequencing has greatly improved the diagnostic success rates for genetic neuromuscular disorders (NMDs). Nevertheless, most patients still remain undiagnosed, and there is a need to maximize the diagnostic yield. METHODS: A retrospective study was conducted on 72 patients with NMDs who underwent exome sequencing (ES), partly followed by genotype-guided diagnostic reassessment and secondary investigations. The diagnostic yields that would have been achieved by appropriately chosen narrow and comprehensive gene panels were also analysed. RESULTS: The initial diagnostic yield of ES was 30.6% (n = 22/72 patients). In an additional 15.3% of patients (n = 11/72) ES results were of unknown clinical significance. After genotype-guided diagnostic reassessment and complementary investigations, the yield was increased to 37.5% (n = 27/72). Compared to ES, targeted gene panels (<25 kilobases) reached a diagnostic yield of 22.2% (n = 16/72), whereas comprehensive gene panels achieved 34.7% (n = 25/72). CONCLUSION: Exome sequencing allows the detection of pathogenic variants missed by (narrowly) targeted gene panel approaches. Diagnostic reassessment after genetic testing further enhances the diagnostic outcomes for NMDs.

Identification of odors, faces, cities and naming of objects in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer´s disease: a longitudinal study.

ABSTRACTObjective:Recent studies have tried to find a reliable way of predicting the development of Alzheimer´s Disease (AD) among patients with mild cognitive impairment (MCI), often focusing on olfactory dysfunction or semantic memory. Our study aimed to validate these findings while also comparing the predictive accuracy of olfactory and semantic assessments for this purpose. METHOD: Six hundred fifty patients (median age 68, 58% females) including controls, SCD (subjective cognitive decline), non-amnestic MCI (naMCI), amnestic MCI (aMCI), and AD patients were tested for olfactory dysfunction by means of odor identification testing and semantic memory. Of those 650 patients, 120 participants with SCD, naMCI, or aMCI at baseline underwent a follow-up examination after two years on average. Of these 120 patients, 12% had developed AD at follow-up (converters), while 88% did not develop AD at follow-up (non-converters). RESULTS: Analysis showed a significant difference only for initial olfactory identification between converters and non-converters. Sensitivity of impairment of olfactory identification for AD prediction was low at 46.2%, although specificity was high at 81.9%. Semantic memory impairment at baseline was not significantly related to AD conversion, although, when naming objects, significant differences were found between AD patients and all other groups and between naMCI and aMCI patients compared to controls and SCD patients. CONCLUSIONS: Objective olfactory assessments are promising instruments for predicting the conversion to AD among MCI patients. However, due to their low sensitivity and high specificity, a combination with other neuropsychological tests might lead to an improved predictive accuracy. Further longitudinal studies with more participants are required to investigate the usefulness of semantic memory tests in this case.

Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia (SPG30) in a few cases. METHODS: All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation. RESULTS: A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found (NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30. CONCLUSIONS: This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases.

Semantic memory and depressive symptoms in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease.

BACKGROUND: Semantic memory may be impaired in clinically recognized states of cognitive impairment. We investigated the relationship between semantic memory and depressive symptoms (DS) in patients with cognitive impairment. METHODS: 323 cognitively healthy controls and 848 patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia were included. Semantic knowledge for famous faces, world capitals, and word vocabulary was investigated. RESULTS: Compared to healthy controls, we found a statistically significant difference of semantic knowledge in the MCI groups and the AD group, respectively. Results of the SCD group were mixed. However, two of the three semantic memory measures (world capitals and word vocabulary) showed a significant association with DS. CONCLUSIONS: We found a difference in semantic memory performance in MCI and AD as well as an association with DS. Results suggest that the difference in semantic memory is due to a storage loss rather than to a retrieval problem.

The impact of depressive symptoms on health-related quality of life in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease.

BACKGROUND: Health-related quality of life (HRQOL) is an important issue in the context of dementia care. The purpose of this study was to investigate the association between HRQOL and depressive symptoms in patients with subjective cognitive decline (SCD) and subtypes of mild cognitive impairment (MCI) and Alzheimer´s disease (AD). METHODS: In this cross-sectional, observational study, a control group and four experimental groups (SCD, non-amnestic MCI, amnesticMCI, AD) were compared. Neuropsychological measurers (NTBV) and psychological questionnaires were used for data collection. RESULTS: The control group scored higher than patients with SCD, naMCI, aMCI, or AD for the Mental Health Component Score (MHCS) of the Short Form of the Health Survey (SF-36). The Physical Health Component Score (PHCS) of the SF-36 differed only between some groups. Furthermore, cognitive variables were more strongly associated with the physical aspects of HRQOL, whereas depressive symptoms were more strongly related with the mental aspects of HRQOL. CONCLUSIONS: HRQOL and depressive symptoms are closely related in patients with cognitive impairments. Therefore, it is of great importance to assess patients with subjective impairment carefully in terms of depressive symptoms.

Homocysteine - A predictor for five year-mortality in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia.

BACKGROUND: Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) are preclinical stages of Alzheimer's Disease (AD), which is the most common entity of dementia. Homocysteine is an amino acid in the methionine cycle, and many studies revealed a significant association between elevated homocysteine serum levels and the progression of dementia. The primary objective of this retrospective study was to investigate whether elevated homocysteine serum levels could be associated with mortality and neuropsychological test results in individuals suffering from SCD, MCI or AD. METHODS: This study is a single-center explorative retrospective data analysis with 976 data protocols from the Memory Outpatient's Clinic of the Medical University of Vienna included. All patients underwent a neurological examination, a laboratory blood test, and neuropsychological testing to establish a diagnosis of either SCD, MCI, or AD. Data was evaluated by Kaplan-Meier functions, factor analysis, and binary logistic regression models. RESULTS: Patients with AD showed significantly higher mean homocysteine levels (SCD 12.15 ± 4.71, MCI 12.80 ± 4.81, AD 15.0 ± 6.44 µmol/L) compared to those with SCD and MCI (p ≤ .001). The mean age of patients with AD (75.2 ± 7.8) was significantly older at the time of testing than of patients with MCI (69.1 ± 9.6) or SCD (66.8 ± 9.3). Since homocysteine levels increase with age, this could be a possible explanation for the higher levels of AD patients. The age at death did not differ significantly between all diagnostic subgroups, resulting in the shortest survival times for AD patients. Homocysteine levels were negatively associated with in Mini-Mental State Examination (MMSE) and Neuropsyhcological Test Battery Vienna (NTBV) factors F1-F4 (F1 = attention, F2 = memory, F3 = executive functions, F4 = naming/verbal comprehension). Moreover, higher homocysteine levels significantly predicted shorter five-year survival in the logistic regression models, even after adjusting for age, diagnostic subgroups, sex, years of education and results of neuropsychological testing. CONCLUSION: The results of this study suggest that homocysteine levels are independently associated with impaired cognitive function and increased five-year mortality.

Hemoglobin A1c Serum Level Predicts 5-year Mortality in Patients with Cognitive Impairment.

Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) may occur as preclinical stages of Alzheimer's disease (AD), ultimately leading to dementia. Glycated hemoglobin A1c (HbA1c) is a diagnostic marker for diabetes mellitus and indicates mortality risk. Objectives: This university-based, exploratory retrospective study examined the impact of HbA1c serum level on 5-year mortality among individuals with cognitive impairment. Methods: Included were 1076 subjects aged at least 50 years who visited the Memory Outpatient Clinic of the Medical University of Vienna due to memory problems. Participants were diagnosed with SCD, MCI, or AD subsequent to neurological examination, standard laboratory blood tests, and neuropsychological testing. Survival was compared between diagnostic subgroups and with respect to HbA1c categories using log-rank tests based on Kaplan-Meier functions. The Neuropsychological Test Battery Vienna (NTBV) was dimensionally reduced, and a principal component analysis (PCA) was performed to further analyze results. Corresponding factor scores, HbA1c values, and baseline characteristics were included in Cox proportional hazards models to assess 5-year mortality risk. Results: During the observation period, 323 patients (30%) died at a mean age comparable between diagnostic subgroups (SCD 84.2 ± 10.1, MCI 81.2 ± 8.3, AD 82.2 ± 7.4 years). Individuals with normal serum HbA1c levels had significant advantages in survival within the MCI (12.9 ± .3 vs. 10.0 ± .8 years) and the AD subgroups (8.2 ± .4 vs. 5.5 ± .6 years), and metric HbA1c predicted 5-year mortality (HR 1.24). Conclusion: This study demonstrates an association between abnormal HbA1c serum levels and increased mortality.

A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7.

A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.

OBJECTIVE: Our aim was to investigate whether the risk of febrile seizures is influenced by a common functional polymorphism in the sodium channel gene SCN1A. This single nucleotide polymorphism (IVS5N+5 G>A, rs3812718) was shown to modify the proportion of two alternative transcripts of the channel. METHODS: We performed an exploratory case-control association analysis in 90 adult epilepsy patients with childhood febrile seizures vs 486 epilepsy patients without a history of febrile seizures and also vs 701 population controls. In the replication step, we investigated children with febrile seizures without concomitant epilepsy at the time of their inclusion. We compared the genotypes of 55 of those children against population controls and performed a within-family association analysis in an additional 88 child-parent trios with febrile seizures. RESULTS: We observed a significant association of the splice-site interrupting A-allele with febrile seizures (p value in the exploratory step: 0.000017; joint p value of the replication: 0.00069). Our data suggest that the A-allele of this variant confers a threefold genotype relative risk in homozygotes and accounts for a population attributable fraction of up to 50% for the etiology of febrile seizures. CONCLUSIONS: The A-allele of the SCN1A single nucleotide polymorphism IVS5N+5 G>A (rs3812718) represents a common and relevant risk factor for febrile seizures. A limitation of the present study is that patients of the exploratory and replication steps differed in aspects of their phenotype (febrile seizures with and without additional epilepsy).

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

Andreas Rett and benign familial neonatal convulsions revisited.

In 1964 Andreas Rett published the first account of a family with benign familial neonatal convulsions (BFNC). The authors retraced Rett's family and report that the clinical and genetic features of this original family fit the currently accepted definitions of BFNC. They also consider the career of Dr. Rett, a researcher and social reformer as well as an advocate for the rights of children with developmental disabilities.

Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.

Mutations in the chloride channel gene CLCN2 have been reported in families with generalized and focal epilepsy syndromes. To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background. No definite mutations were found in our study population. We conclude that mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy.

Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy.

The multidrug transporter P-glycoprotein is suspected of contributing to pharmacoresistance in temporal lobe epilepsy (TLE). To assess the role of functional variations in its coding gene (ABCB1) the authors genotyped 210 patients with TLE who were stratified according to their degree of drug resistance. They identified a common haplotype that when present in the homozygous state significantly increased the risk for pharmacoresistance.